Search Results (289)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) pathology, synaptic degeneration, impaired neurogenesis, and chronic neuroinflammation. KBN2202, a small-molecule salicylic acid derivative [2-[(2-naphthalen-1-yloxy)ethyl]amino]-4-hydroxybenzoic acid], was investigated for its potential as a multi-target therapeutic agent in advanced-stage AD. To this end, 9-month-old 5xFAD mice with established AD-like pathology received daily oral KBN2202 (5 or 20 mg/kg) or vehicle for 12 weeks. KBN2202 demonstrated broad histopathological benefits. It preserved hippocampal CA1 cytoarchitecture and increased dendritic length in cortical neurons. Neurogenic activity was also enhanced, with elevated doublecortin (DCX) expression in the subventricular zone (SVZ). At the molecular level, KBN2202 reduced amyloid precursor protein C-terminal fragments (APP-CTFs), key intermediates in amyloidogenic processing, and histological staining confirmed a significant reduction in fibrillar and diffuse Aβ plaque burden in the cortex and hippocampus. Furthermore, KBN2202 attenuated astrocytic and microglial activation, indicating suppression of chronic neuroinflammation. In behavioral assessments, KBN2202 significantly improved recognition memory in the novel object recognition (NOR) test, while Y-maze performance remained unchanged. Overall, the compound exhibited robust neuroprotective, pro-neurogenic, anti-amyloid, and anti-inflammatory effects. These findings support the therapeutic potential of KBN2202 as a multi-functional candidate for symptomatic-stage AD. Full article

The identification of brain clearance failure as a precursor to a large variety of neurodegenerative diseases has shifted fluid dynamics from a secondary to a tertiary target of brain health. The identification of the glymphatic system, detailing cerebrospinal fluid entry along perivascular spaces and exit via perivenous and meningeal lymphatic pathways, provided a challenge to previous diffusion models and established aquaporin-4–dependent astroglial polarity as a governing principle of solute transport. Multiple lines of evidence now support a coupled glymphatic–venous axis, wherein vasomotion, venous outflow, and lymphatic drainage are functionally interrelated. Failure of any axis will cascade and affect the entire axis, linking venous congestion, aquaporin-4 disassembly, and meningeal lymphatic failure to protein aggregation, neuroinflammation, edema, and intracranial hypertension. Specific lines of evidence from diffusion tensor imaging along vascular spaces, clearance MRI, and multi-omic biomarkers can provide a measure of transport. Therapeutic strategies are rapidly advancing from experimental strategies to translational approval, including behavioral optimization, closed-loop sleep stimulation, vascular and lymphatic therapies, focused ultrasound, pharmacological polarity recoupling, and regenerative bioengineering. Novel computational approaches, such as digital twin dynamic modeling and adaptive trial designs, suggest that clearance measures may serve as endpoints to be approved by the FDA. This review is intended to bridge relevant mechanistic and translational reviews, focusing on impaired clearance as an exploitable systems defect rather than an incapacitating secondary effect. Improving our understanding of the glymphatic-venous axis Injury may lead to future target strategies that advance cognitive resilience, alleviate disease burden, and improve quality of life. By clarifying the glymphatic–venous axis, we provide a mechanistic link between impaired interstitial clearance and the pathological accumulation of amyloid-β, tau, and α-synuclein in neurodegenerative diseases. The repair of aquaporin-4 polarity, venous compliance, and lymphatic drainage might therefore open new avenues for the diagnosis and treatment of Alzheimer’s and Parkinson’s disease, supplying both biomarkers of disease progression and new targets for early intervention. These translational implications not only locate clearance failure as an epiphenomenon of neurodegeneration but, more importantly, as a modifiable driver of the course of neurodegeneration. Full article

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and neurodegeneration. Since the amyloid cascade hypothesis was proposed, Aβ has remained a central therapeutic target, with interventions aiming to reduce Aβ production, aggregation, or downstream toxicity. This review first outlines the historical development of the Aβ hypothesis and the two major APP processing pathways (α-cleavage and β-cleavage), highlighting the role of biomarkers in early diagnosis, patient stratification, and regulatory approval. We then summarize the development and clinical outcomes of anti-Aβ small-molecule drugs, including β-secretase inhibitors, γ-secretase modulators, Aβ aggregation inhibitors, receptor/synapse modulators, and metabolic or antioxidant modalities. We further review the progression of biologic therapies, with a particular focus on monoclonal antibodies, vaccines, and emerging gene-silencing strategies, such as small interfering RNA (siRNA) and antisense oligonucleotides. Finally, we discuss future perspectives, including next-generation biologics, multi-target approaches, optimized delivery platforms, and early-prevention strategies. Collectively, these efforts underscore both the challenges and opportunities in translating anti-Aβ therapies into meaningful clinical benefits for patients with AD. Full article

Butylparaben (BP), a widely used preservative, was implicated in cognitive impairment, though its neurotoxic mechanisms remain elusive. Basal forebrain cholinergic neurons (BFCN) are selectively lost in dementias, contributing to cognitive decline. To explore different mechanisms related with BFCN loss, we employed BF SN56 cholinergic wild-type or silenced cells for Tau, amyloid-beta precursor protein (βApp), acetylcholinesterase (AChE), or glycogen synthase kinase-3 beta (GSK3β) genes, exposing them to BP (0.1–80 µM) for 1 or 14 days alongside triiodothyronine (T3; 15 nM), N-acetylcysteine (NAC; 1 mM), or recombinant heat shock protein 70 (rHSP70; 30 µM). BP disrupted cholinergic transmission by AChE inhibition and provoked cell death through thyroid hormones (THs) pathway disruption, Aβ/p-Tau protein accumulation, AChE-S overexpression, and oxidative stress (OS). Aβ/p-Tau accumulation was correlated with HSP70 downregulation, OS exacerbation, and GSK3β hyperactivation (for p-Tau). BP-induced OS was mediated by reactive oxygen species (ROS) overproduction and nuclear factor erythroid 2-related factor 2 (NRF2) pathway disruption. All observed effects were contingent upon TH signaling impairment. These findings uncover novel mechanistic links between BP exposure and BFCN neurodegeneration, providing a framework for therapeutic strategies. Full article

Alzheimer’s disease (AD), the most prevalent form of dementia, poses a critical global health challenge as its incidence rises with aging populations. Despite extensive research into its genetic and molecular underpinnings, effective therapeutic strategies remain limited. Growing evidence suggests that physical exercise may offer neuroprotective benefits, potentially mitigating AD progression through multifactorial mechanisms. This review synthesizes current findings on the interplay between aerobic exercise and AD pathophysiology, with a focus on amyloid-β (Aβ) metabolism, gene expression, and neuroinflammation. We explore how exercise influences Aβ clearance, modulates amyloid precursor protein (APP) processing, and impacts the activity of key enzymes such as secretases and neprilysin. Further, we highlight the gene–exercise crosstalk identified through transcriptomic data, particularly in the entorhinal cortex—an early site of Aβ deposition. Our analysis also discusses how exercise-induced modulation of molecular pathways—including mitochondrial function, oxidative stress responses, and neuroinflammatory cascades—may confer cognitive resilience. By integrating molecular, genetic, and systems biology data, this review underscores the potential of structured physical activity as a non-pharmacological intervention to delay or attenuate AD pathology. These insights support a precision medicine approach, which combines lifestyle interventions with molecular profiling, to improve prevention strategies and therapeutic outcomes in AD. Full article

Both epidemiological and animal model studies have revealed that heat stroke is closely related to the development or exacerbation of dementia disorders. The most common form of dementia is Alzheimer’s disease, which is characterized by the accumulation of amyloid-β protein in the central nervous system. Notably, a whole-genome transcriptome analysis of heat stroke patients has identified the increased expression of amyloid-β precursor protein gene and the activation of amyloid processing pathways. This finding provides a molecular basis for the theory that heat stroke is a risk factor for dementia disorders. Down syndrome—a common chromosomal abnormality—is also a dementia disorder that is characterized by the overexpression of amyloid-β precursor protein gene and the accumulation of amyloid-β protein. Thus, heat stroke may also develop or exacerbate Alzheimer’s disease-like dementia in Down syndrome. For individuals with Down syndrome, heat stroke is therefore not only a life-threatening risk factor but may also be a risk factor for accelerating intellectual decline. Full article

Background/Objectives: The accumulation of Nε-carboxymethyllysine (CML), a major advanced glycation end product (AGE), has been implicated in neuronal dysfunction by promoting oxidative stress, endoplasmic reticulum (ER) stress, and dysregulation of amyloid-β (Aβ) metabolism. This study evaluated the neuroprotective properties of coixol, a naturally occurring polyphenolic compound derived from the outer layers of Coix lacryma-jobi L. var. ma-yuen, in a CML-induced injury model using IMR-32 human neuronal-like cells. Methods: Cells were pretreated with coixol (1 μmol/L), N-acetyl-L-cysteine (NALC, 1 mmol/L), or 4-phenylbutyric acid (4-PBA, 200 μmol/L) for 1 h prior to CML (100 μmol/L) exposure for 24 h. Cell viability was determined by colorimetric analysis of 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide, while intracellular reactive oxygen species (ROS) generation was quantified using a fluorescence-based oxidative stress probe. Activities of key antioxidant enzymes and caspase-3 were determined using commercial assay kits. The expression of Aβ isoforms, amyloidogenic enzymes, ER stress markers, and apoptosis-related signaling proteins was quantified through validated immunoassays. Results: Coixol pretreatment significantly enhanced cell viability by attenuating ROS accumulation and restoring antioxidant enzyme activities. Concurrently, coixol suppressed ER stress signaling via downregulation of the protein kinase R-like ER kinase/C/EBP homologous protein axis and modulated apoptosis by increasing B-cell lymphoma (Bcl)-2, reducing Bcl-2-associated X protein expression, and inhibiting caspase-3 activation and DNA fragmentation. Furthermore, coixol regulated Aβ metabolism by inhibiting the expression of β-site amyloid precursor protein-cleaving enzyme 1 and presenilin 1, while restoring insulin-degrading enzyme and neprilysin levels, leading to reduced accumulation of Aβ40 and Aβ42. Conclusions: Compared to NALC and 4-PBA, coixol demonstrated comparable or superior modulation across multiple pathological pathways. These findings highlight coixol’s potential as a neuroprotective candidate in AGE-associated neurodegenerative conditions. Full article

The matrix metalloproteinase (MMP) family includes several membrane-bound enzymes. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is unique amongst the MMP family in being primarily expressed in the brain and during development. It is proposed to contribute to synaptic plasticity and is implicated in several pathologies, including multiple cancers and Alzheimer’s disease. In cancer, MT5-MMP expression has been correlated to cancer progression, but a distinct mechanistic role has yet to be uncovered. In Alzheimer’s disease, MT5-MMP exhibits pro-amyloidogenic activity, functioning as an η-secretase that cleaves amyloid precursor protein (APP), ultimately generating two synaptotoxic fragments, Aη-α and Aη-β. Several intracellular binding partners for MT5-MMP have been identified, and of these, N4BP2L1, EIG121, BIN1, or TMX3 binding to MT5-MMP results in a significant increase in MT5-MMP η-secretase activity. Beyond direct effects on APP, MT5-MMP may also facilitate APP trafficking to endosomal/lysosomal compartments and enhance proinflammatory responses. Overall, the substrate profile of MT5-MMP has not been well defined, and selective inhibitors of MT5-MMP have not been described. These advances will be needed for further consideration of MT5-MMP as a therapeutic target in Alzheimer’s disease and other pathologies. Full article

Familial Alzheimer’s disease (FAD) is caused by dominant missense mutations in amyloid precursor protein (APP) and presenilin-1 (PSEN1), the catalytic component of γ-secretase that generates amyloid β-peptides (Aβ) from the APP C-terminal fragment C99. While most FAD mutations increase the ratio of aggregation-prone Aβ42 relative to Aβ40, consistent with the amyloid hypothesis of Alzheimer pathogenesis, some mutations do not increase this ratio. The γ-secretase complex produces amyloid β-peptide (Aβ) through processive cleavage along two pathways: C99 → Aβ49 → Aβ46 → Aβ43 → Aβ40 and C99 → Aβ48 → Aβ45 → Aβ42 → Aβ38. Understanding how FAD mutations affect the multistep γ-secretase cleavage process is critical for elucidating disease pathogenesis. In a recent study, we discovered that FAD mutations lead to stalled γ-secretase/substrate complexes that trigger synaptic loss independently of Aβ production. Here, we further investigate this “stalled complex” hypothesis, focusing on five additional PSEN1 FAD mutations (M84V, C92S, Y115H, T116I, and M139V). A comprehensive biochemical analysis revealed that all five mutations led to substantially reduced initial proteolysis of C99 to Aβ49 or Aβ48 as well as deficiencies in one or more subsequent trimming steps. Results from fluorescence lifetime imaging microscopy support increased stabilization of enzyme–substrate complexes by all five FAD mutations. These findings provide further support for the stalled complex hypothesis, highlighting that FAD mutations impair γ-secretase function by promoting the accumulation of stalled enzyme–substrate complexes. Full article

Iron accumulation in the brain is widespread in Alzheimer’s disease (AD), the most common cause of dementia. According to numerous studies, too much iron triggers the development of neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques, both of which accelerate the onset of AD. Iron sequestration and storage were disrupted by high iron, and the pattern of interaction between iron regulatory proteins (IRPs) and iron-responsive elements (IREs) was altered. The 5′-untranslated regions (5′-UTRs) of their APP mRNA transcripts have an IRE stem-loop, which is where iron influx enhances the translation of the amyloid precursor protein (APP). Iron regulated APP expression via the release of the repressor interaction of APP mRNA with IRP1 by a pathway similar to the iron control translation of the ferritin mRNA by the IREs in their 5′-UTRs. This leads to an uncontrolled buildup of redox active Fe²⁺, which exacerbates neurotoxic oxidative stress and neuronal death. Fe²⁺ overload upregulates the APP expression and increases the cleavage of APP and the accumulation of Aβ in the brain. The level of APP and Aβ, and protein aggregates, can be downregulated by IRPs, but are upregulated in the presence of iron overload. Therefore, the inhibition of the IRE-modulated expression of APP or Fe²⁺ chelation offers therapeutic significance to AD. In this article, I discuss the structural and functional features of IRE in the 5′-UTR of APP mRNA in relation to the cellular Fe²⁺ level, and the link between iron and AD through the amyloid translational mechanism. Although there are currently no treatments for AD, a progressive neurodegenerative disease, there are a number of promising RNA inhibitor and Fe²⁺ chelating agent therapeutic candidates that have been discovered and are being validated in April 2025 clinical trials. Future studies are expected to further show the therapeutic efficacy of iron-chelating medications, which target the APP 5′-UTR and have the ability to lower APP translation and, consequently, Aβ levels. As a result, these molecules have a great deal of promise for the development of small-molecule RNA inhibitors for the treatment of AD. Full article

Chronic periodontitis, driven by the keystone pathogen Porphyromonas gingivalis, has been increasingly associated with Alzheimer’s disease (AD) and AD-related dementias (ADRDs). However, the mechanisms through which P. gingivalis-lipopolysaccharide (LPS)-induced release of neuroinflammatory proteins contribute to the pathogenesis of AD and ADRD remain inadequately understood. Caspase-4, a critical mediator of neuroinflammation, plays a pivotal role in these processes following exposure to P. gingivalis-LPS. In this study, we investigated the mechanistic role of caspase-4 in P. gingivalis-LPS-induced IL-1β production, neuroinflammation, oxidative stress, and mitochondrial alterations in human neuronal and microglial cell lines. Silencing of caspase-4 significantly attenuated IL-1β secretion by inhibiting the activation of the caspase-4-NLRP3-caspase-1-gasdermin D inflammasome pathway, confirming its role in neuroinflammation. Moreover, caspase-4 silencing reduced the activation of amyloid precursor protein and presenilin-1, as well as the secretion of amyloid-β peptides, suggesting a role for caspase-4 in amyloidogenesis. Caspase-4 inhibition also restored the expression of key neuroinflammatory markers, such as total tau, VEGF, TGF, and IL-6, highlighting its central role in regulating neuroinflammatory processes. Furthermore, caspase-4 modulated oxidative stress by regulating reactive oxygen species production and reducing oxidative stress markers like inducible nitric oxide synthase and 4-hydroxynonenal. Additionally, caspase-4 influenced mitochondrial membrane potential, mitochondrial biogenesis, fission, fusion, mitochondrial respiration, and ATP production, all of which were impaired by P. gingivalis-LPS but restored with caspase-4 inhibition. These findings provide novel insights into the role of caspase-4 in P. gingivalis-LPS-induced neuroinflammation, oxidative stress, and mitochondrial dysfunction, demonstrating caspase-4 as a potential therapeutic target for neurodegenerative conditions associated with AD and related dementias. Full article

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders linked to aging. Major hallmarks of AD pathogenesis include amyloid-β peptide (Aβ) plaques, which are extracellular deposits originating from the processing of the amyloid precursor protein (APP), and neurofibrillary tangles (NFTs), which are intracellular aggregates of tau protein. Recent evidence indicates that disruptions in metal homeostasis and impaired immune recognition of these aggregates trigger neuroinflammation, ultimately driving disease progression. Therefore, a more comprehensive approach is needed to understand the underlying causes of the disease. Patients with AD present abnormal glycan profiles, and most known AD-related molecules are either modified with glycans or involved in glycan regulation. A deeper understanding of how O-glycosylation influences the balance between amyloid-beta peptide production and clearance, as well as microglia’s pro- and anti-inflammatory responses, is crucial for deciphering the early pathogenic events of AD. This review aims to provide a comprehensive summary of the extensive research conducted on the role of mucin-type O-glycosylation in the pathogenesis of AD, discussing its role in disease onset and immune recognition. Full article

Background/Objectives: Diabetic encephalopathy (DE), a severe neurological complication of diabetes mellitus (DM), is characterized by cognitive dysfunction. 3-Methyladenine (3-MA), a methylated adenine derivative, acts as a biomarker for DNA methylation and exhibits hypoglycemic and neuroprotective properties. However, the pharmacological mechanisms underlying 3-MA’s therapeutic effects on diabetic microvascular complications remain incompletely understood, owing to the intricate and multifactorial pathogenesis of DE. Methods: This study employed network pharmacology and molecular docking techniques to predict potential targets and signaling pathways of 3-MA against DE, with subsequent validation through animal experiments to elucidate the molecular mechanisms of 3-MA in DE treatment. Results: Network pharmacological analysis identified two key targets of 3-MA in DE modulation: AKT and GSK3β. Molecular docking confirmed a strong binding affinity between 3-MA and AKT/GSK3β. In animal experiments, 3-MA significantly reduced blood glucose levels in diabetic mice, ameliorated learning and memory deficits, and preserved hippocampal neuronal integrity. Furthermore, we found that 3-MA inhibited apoptosis by regulating the expression of Bax and BCL-2. Notably, 3-MA also downregulated the expression of amyloid precursor protein (APP) and Tau while enhancing the expression of phosphorylated AKT and GSK-3β. Conclusions: Our findings may contribute to elucidating the therapeutic mechanisms of 3-MA in diabetic microangiopathy and provide potential therapeutic targets through activation of the AKT/GSK-3β pathway. Full article

Background/Objectives: Alterations of oxysterols and gut microbiota have been recognized as indicators affecting mild cognitive impairment (MCI) and sarcopenia, respectively, whereas their association with co-dysfunction has not been investigated. Methods: In this study, a total of 1035 individuals were divided into Control (n = 264), MCI (n = 435), and MCI with possible sarcopenia (MPS, n = 336) groups. Cognition and muscle indexes, serum oxysterols, and gut microbiota were measured. Spearman’s rank coefficients were calculated to determine their correlations. Results: Performances of global and multidimensional cognitive tests was successively worse in the Control, MCI, and MPS groups. Longer duration of five-time chair stand test, lower 6-meter walk speed, and handgrip strength were observed in the MPS group, along with increased 27-hydroxycholesterol (27-OHC) and 5α,6α-epoxycholesterol and decreased 5α-Cholest-8(14)-ene-3β,15α-diol (15-HC). Higher concentrations of amyloid precursor protein (APP), neurofilament, and C-terminal agrin fragment (CAF) were discovered in the MCI and MPS groups. The α-diversity of gut microbiota in the MCI and MPS group was remarkably decreased, followed by a shifted abundance of microbial taxa, such as Alistipes and Rikenellaceae. Multiple significant correlations were found between cognition and muscle indexes and with oxysterols. Conclusions: Our study indicates that oxysterols and gut microbiota are prominently involved in the co-dysfunction of cognition and muscle. Full article

Innovations in spinal cord injury (SCI) models are crucial for developing effective therapies. This study introduces a novel in vitro SCI model using cultures of primary mixed spinal cord cells from rat pups, featuring key spinal cord cell types. This model offers distinct advantages in terms of feasibility, reproducibility, and cost-effectiveness, requiring only basic cell culture equipment. Following hyperosmotic stress via sorbitol treatment, the model recapitulated SCI pathophysiological hallmarks, with a 65% reduction in cell viability and gradual cell death over 48 h, making it ideal for evaluating neuroprotective agents. Notably, the human adipose tissue stem cell (hASC) secretome provided significant protection: it preserved metabolic viability, reduced β amyloid precursor protein (β-APP) expression in surviving neurons, and modulated the shift in the astrocytic morphotype. A transcriptomic profile of the effect of the hASC secretome treatment showed significant functional enrichments related to cell proliferation and cycle progression pathways. In addition to supporting the use of the hASC secretome as a therapy for SCI, this study is the first to use sorbitol as a hyperosmolar stressor to recapitulate key aspects of SCI pathophysiology. Thereby, this model can be used as a promising platform for evaluating therapeutic agents targeting neuroprotection and neuroregeneration, offering outputs related to cell death, neuronal stress, and protection, as well as induction of glial reactivity. Full article